Pharmacodynamic Activity of Telithromycin at Simulated Clinically Achievable Free-Drug Concentrations in Serum and Epithelial Lining Fluid against Efflux ( mefE )-Producing Macrolide- Resistant Streptococcus pneumoniae for Which Telithromycin MICs Vary

Abstract

The present study, using an in vitro model, assessed telithromycin pharmacodynamic activity at simulated clinically achievable free-drug concentrations in serum (S) and epithelial lining fluid (ELF) against efflux (mefE)-producing macrolide-resistant Streptococcus pneumoniae. Two macrolide-susceptible (PCR negative for both mefE and ermB) and 11 efflux-producing macrolide-resistant [PCR-positive for mefE and negative for ermB) S. pneumoniae strains with various telithromycin MICs (0.015 to 1 g/ml) were tested. The steady-state pharmacokinetics of telithromycin were modeled, simulating a dosage of 800 mg orally once daily administered at time 0 and at 24 h (free-drug maximum concentration [C max ] in serum, 0.7 g/ml; half-life [t 1/2 ], 10 h; free-drug C max in ELF, 6.0 g/ml; t 1/2 , 10 h). Starting inocula were 10 6 CFU/ml in Mueller-Hinton Broth with 2% lysed horse blood. Sampling at 0, 2, 4, 6, 12, 24, and 48 h assessed the extent of bacterial killing (decrease in log 10 CFU/ml versus initial inoculum). Free-telithromycin concentrations in serum achieved in the model were C max 0.9 ؎ 0.08 g/ml, area under the curve to MIC (AUC 0-24 h ) 6.4 ؎ 1.5 g · h/ml, and t 1/2 of 10.6 ؎ 0.6 h. Telithromycin-free ELF concentrations achieved in the model were C max 6.6 ؎ 0.8 g/ml, AUC 0-24 h 45.5 ؎ 5.5 g · h/ml, and t 1/2 of 10.5 ؎ 1.7 h. Free-telithromycin S and ELF concentrations rapidly eradicated efflux-producing macrolide-resistant S. pneumoniae with telithromycin MICs up to and including 0.25 g/ml and 1 g/ml, respectively. Free-telithromycin S and ELF concentrations simulating C max /MIC > 3.5 and AUC 0-24 h /MIC > 25 completely eradicated (>4 log 10 killing) macrolide-resistant S. pneumoniae at 24 and 48 h. Free-telithromycin concentrations in serum simulating C max /MIC > 1.8 and AUC 0-24 h /MIC > 12.5 were bacteriostatic (0.1 to 0.2 log 10 killing) against macrolide-resistant S. pneumoniae at 24 and 48 h. In conclusion, free-telithromycin concentrations in serum and ELF simulating C max /MIC > 3.5 and AUC 0-24 h /MIC > 25 completely eradicated (>4 log 10 killing) macrolide-resistant S. pneumoniae at 24 and 48 h.Macrolide (azithromycin, clarithromycin, and erythromycin) resistance in Streptococcus pneumoniae is presently ϳ25% in the United States and approximately 13% in Canada (1,3,28,31). Macrolide resistance in S. pneumoniae involves alteration of the ribosomal target site or production and utilization of an efflux mechanism (6, 9, 29, 33). The production of ribosomal methylase, which alters the ribosomal target site of the macrolide, is usually coded for by the ermB gene and confers broad macrolide, lincosamide, and streptogramin B resistance (6, 9, 29, 33). The second mechanism, which results in macrolide efflux, is coded by the mefA or mefE genes (6,9,29,33). Efflux is macrolide specific (14-and 15-membered macrolides only) and does not affect the lincosamide or streptogramins (28,32). Note that ermB-positive S. pneumoniae strains generally exhibit high-level (MIC 90 Ն 64 g/ml) macrolide resistance, while mefA...

In Vitro Pharmacokinetic and Pharmacodynamic Evaluation of S-013420 against Haemophilus influenzae and Streptococcus pneumoniae

“…One erythromycin-susceptible S. pneumoniae isolate and two erythromycin-resistant S. pneumoniae isolates, including mefA-positive and ermB-positive strains, were tested (16,21,26,27,29,30). The AUC 0-24 /MIC values of S-013420 required for activity against S. pneumoniae were determined.…”

“…This result is supported by characterization of the concentration-dependent bactericidal activity of S-013420 which was indicated by timekill kinetics (12a). As for S. pneumoniae, other studies of macrolide antibiotics also showed that AUC 0-24 /MIC was the dominant parameter which correlated with antibacterial activity and characterized concentration-dependent bactericidal activity (16,21,26,27,29,30). The dominant PK/PD parameter for determination of the efficacy of macrolide antimicrobials was considered to be AUC/MIC, regardless of the bacterial species.…”

“…Zhanel et al suggested that telithromycin concentrations simulating an AUC 0-24 /MIC of Ն25 caused the complete eradication of S. pneumoniae (29) and azithromycin concentrations simulating an AUC 0-24 /MIC of Ն36.7 were bactericidal (30) against S. pneumoniae. In this study, the AUC 0-24 /MIC values of S-013420 for maximal efficacy against S. pneumoniae were 16.3 to 22.3, which were similar to those of telithromycin and azithromycin.…”

“…These three parameters (1) are the area under the concentration-time curve from 0 to 24 h (AUC 0-24 )/MIC, the peak concentration (C max )/MIC, and the cumulative percentage of a 24-h period that the drug concentration exceeds the MIC under steady-state PK conditions (%T MIC ). Nonclinical PK/PD characterizations of antimicrobials using in vitro PD models or in vivo infection models have been reported (2,5,26,29). In general, AUC 0-24 /MIC is the dominant PK/PD parameter for macrolides, ketolides, and quinolones, while C max /MIC is the main parameter for quinolones and aminoglycosides and %T MIC is that for ␤-lactams (1, 4).…”

Macrolides and Ketolides

“…For telithromycin, a bactericidal effect was observed when simulated concentrations in serum and epithelial lining allowed to reach a C max /MIC ≥ 3.5 and an area under the curve to MIC ≥ 25 h, but a bacteriostatic effect was observed when these exposures were twice lower. This means that telithromycin at its conventional dosage should be able to eradicate streptococci with an MIC of 0.25 mg L −1 in serum and 1 mg L −1 in epithelial lining fl uid (Zhanel et al 2005 ). This type of approach also led to the conclusion that at human-simulated exposure, telithromycin can achieve higher AUC/MIC ratios than clarithromycin against S. pneumoniae , and therefore higher chances of microbiological eradication, while the contrary holds true for S. aureus (Alferova et al 2005 ).…”